Hepatitis B virus (HBV) belongs to the class of double stranded DNA viruses and is presently known to include four major serotypes (adr, adw, ayr, and ayw) and eight major genotypes (A though H). The serotypes are based on variations in envelope protein sequences while the eight genotypes are distinctly distributed across the world in specific geographical areas. Genotypic differences have been linked to disease severity and effectiveness of response to treatment (see Kramvis et al., Vaccine, 23(19):2409-23, 2005, and Magnius et al., Intervirology, 38(1-2):24-34, 1995).
The HBV genome is comprised of circular DNA that is partially double stranded. That is, there are portions of the genome that are single stranded. The longer portion of the HBV genome is 3020 to 3320 nucleotides in length, while the shorter portion is 1700 to 2800 nucleotides in length. The longer portion of the HBV genome is linked to the viral DNA polymerase.
HBV-infected cells can produce, in addition to infectious virus particles, spherical and filamentous non-infectious particles lacking a core. These non-infectious particles can outnumber infectious particles in an HBV-infected individual by as much as 1,000 to 100,000 fold (see Chai et al. J. Vivol. 82:7812-7817, 2005).
There are five viral proteins produced by HBV, including the following:                1. Envelope protein (also known as surface antigen, HBsAg, encoded by the S gene);        2. Polymerase (pol, encoded by the P gene);        3. Hepatitis B X-protein (HBxAg, X-antigen, encoded by the X gene);        4. Nucleocapsid or core antigen (HBcAg, encoded by the C gene); and        5. Precore (HBeAg, encoded by the core and Pre-C genes).        
The HBsAg is produced in three sizes from the three independent start codons in the HBV genome. The Small, Medium and Large versions of this gene product are a combination of one or more of the three designated domains: (i) S alone (S), (ii) pre-S2 and S (M), or (iii) pre-S1 and pre-S2 and S (L) (FIG. 1A). Infectious particles most often possess all three versions of this antigen, and can enter hepatocytes via the interaction between pre-S1 protein (FIG. 1B) and the NTCP receptor (sodium taurocholate co-transporting polypeptide, or liver bile acid transporter, encoded by the SLC10A1 gene). Thus, the pre-S1 antigen is associated with infection and is preferentially expressed in infectious viral particles. (Hong et al., Virology, 318:134-141, 2004; Park et al., Antiviral Res., 68:109-115, 2005).
HBeAg is the precore protein and is secreted. The precore protein has been shown to play an immune regulatory role. HBeAg has been found to regulate the immune response to the core antigen. (Chen et al., Proc. Natl. Acad. Sci. USA, 101:14913-14918, 2004).
While the functions of the capsid, polymerase and surface antigen proteins seem clear, the function of the “X” gene has yet to be fully elucidated, though it is known to play a role in the development of hepatocellular carcinoma (HCC). (Tang et al., Cancer Sci., 97:977-983, 2006, Ng et al., J. Gastroent., 46:974-990, 2011, and Kew, Michael C., J. Gastro. Hepat., 26 Suppl. 1:144-152, 2011).
The hepatitis B virus is believed to have infected more than 2 billion people around the world. There are believed to be 350 to 400 million chronically or persistently infected individuals worldwide and HBV or complications from HBV infection results in 780,000 deaths per year worldwide. HBV is fifty to one hundred times more infectious than the human immunodeficiency virus (HIV). HBV is transmitted by exposure to infectious blood or body fluids. Symptoms of infection commonly include loss of appetite, fatigue, a low fever, jaundice, aches in muscles and joints, nausea and vomiting, yellow skin and dark urine. Some individuals are not able to completely clear the virus from their system, resulting in a chronic infection that can result in liver damage and cirrhosis. About 15 to 40% of chronic HBV patients develop liver cirrhosis and/or HCC. (Xu et al., Canc. Lett., 345:216-222, 2014). The HBV viral genome persists in the genome of the host and can be reactivated after being cleared, leading to new HBV symptoms. The rate of liver cancer is much higher in those who have an HBV infection.
Both clearance and pathogenesis of the virus are mediated by the adaptive, or acquired, immune response. This includes both a humoral (antibody-mediated) immunity component and cell-mediated immune component. In particular, infection triggers response of virus-specific cytotoxic T lymphocytes (CTL), which produce most of the observed injury to liver tissue in chronic infections.
Many preventive strategies have been developed to combat HBV infection. Vaccines have been developed based on recombinant surface antigen of the virus. (See, WO 2014/0489101 and Shouval, D., J. Hepatol. 39 (Suppl. 0:70-76, 2003). In addition, an HBV immunoglobulin (HBIG) has been developed from human sera from high titer individuals. HBIG is typically provided to infants of HBV infected mothers to prevent transmission to the child. If HBIG is administered within 24 hours of known exposure, HBV infection can be prevented. HBIG is also commonly administered to HBV infected liver transplant patients to prevent re-infection of the new tissue.
Chronically infected individuals are candidates for therapy. However, there is presently no approved treatment known to clear chronic HBV infection. Available therapies can block further infection by precluding the virus from replicating. Various monoclonal antibodies and combination therapies have been investigated for the purpose of treating and/or curing HBV infection, including chronic HBV infection, but none have been commercialized.
The treatment options for chronic infection, e.g., interferon and lamivudine, are only modestly effective and are known to cause severe side effects. Despite efforts directed toward the development of therapies for treatment or prevention of HBV infection, there remains a continuing need to develop new therapies targeting HBV infection, e.g., chronic HBV infection.